In Diabetes, Get Glucose Control 'Just Right'

Action Points

Explain to interested patients that the American Diabetes Association recommends a hemoglobin A1c treatment target of less than 7% for nonpregnant adults in general with tight glucose control reserved for patients in whom it can be achieved without significant hypoglycemia or other adverse effects of treatment.

Intensive treatment to achieve normoglycemia in type 2 diabetes may be almost as bad for survival and heart health as leaving glucose levels elevated, according to a study of real-world practice.

The study turned up a U-shaped link between all-cause mortality and glycosylated hemoglobin levels in which those at a median of 7.5% carried the lowest risk, found Craig J. Currie, PhD, of Cardiff University in Cardiff, Wales, and colleagues.

By comparison, patients who reached normal glycosylated hemoglobin levels with a median of 6.4% were at 52% greater risk of dying from any cause during the study period (95% confidence interval 32% to 76%).

Those in the highest decile with a median of 10.5% hemoglobin A1c were at 79% elevated risk (95% CI 55% to 106%), the researchers reported online in The Lancet.

"If confirmed, diabetes guidelines might need revision to include a minimum hemoglobin A1c value," they wrote in the study.

Richard Bergenstal, MD, president for medicine and science of the American Diabetes Association, agreed that confirmation would be key and cautioned against overinterpreting the results.

Practice doesn't change based on epidemiological evidence alone, particularly when it fits with only part of the clinical trial literature, he noted.

Among the several recent large clinical trials to examine tight glucose control with hemoglobin A1c goals below the standard 7%, only one showed a negative impact on survival -- 22% excess mortality in the ACCORD trial with an ultra-tight target under 6.0%.

A meta-analysis of the trials suggested no reduction in all-cause or cardiovascular mortality, stroke, amputations, or even microvascular complications with aggressive glycemic control strategies aiming to bring A1c under 7%.

Although the reason behind the elevated mortality in ACCORD remains a mystery, "the most plausible explanation for these results is hypoglycemia: the treatment target was probably too low, or glucose lowering was too rapid, or the combinations of treatments led to hypoglycemia," according to an accompanying editorial in The Lancet.

The new observational data may shed some light on this issue, wrote Beverley Balkau, PhD, and Dominique Simon, MD, PhD, both of the INSERM Center for Research in Epidemiology and Population Health in Villejuif, France.

Currie's group retrospectively reviewed data from medical records of British primary care physicians in the U.K. General Practice Research Database from November 1986 to November 2008.

They identified two cohorts of patients 50 years and older with primary type 2 diabetes: 27,965 whose treatment had been intensified from oral monotherapy to combinations of oral blood-glucose lowering agents, and 20,005 who switched to regimens that included insulin.

Initial hemoglobin A1c levels were 9.0% and 10.0% in the two groups before intensification of treatment.

"This two-cohort approach was intended to establish whether any emergent patterns were independent of diabetes treatment regimen," the researchers explained in The Lancet.

After an average of 4.5 to 5.2 years of follow-up, patients in the lowest and highest deciles of achieved hemoglobin A1c were at elevated risk of death from any cause in both unadjusted and adjusted analyses.

In the cohort treated with oral drugs alone, only the highest and lowest deciles, for whom the median hemoglobin levels were 10.5% and 6.4% respectively, were at elevated risk.

In the group treated with insulin, significantly elevated risk was seen in the three lowest and two highest groups compared with the lowest risk decile (median 7.5% hemoglobin A1c).

The researchers also found the same U-shaped relationship between glucose control and new-onset, large-vessel cardiac disease events.

The lowest hemoglobin A1c group was at 54% increased risk for cardiac events (28% to 84%) while the highest decile was at 36% elevated risk (95% CI 14% to 61%) compared with the group who had a median 7.5% hemoglobin A1c.

One of the risk factors for these hazards appeared to be insulin-based regimens.

Insulin treatment was also associated with 31% elevated likelihood of progression to a first large-vessel disease event (95% CI 22% to 42%).

Since previous studies have shown greater hypoglycemia risk with insulin treatment than with oral agents, such as sulfonylurea therapy, this result further implicates hypoglycemia in the premature death associated with tight glucose control, Balkau and Simon said.

"Priority should be given to insulin sensitisers for as long as possible in patients with type 2 diabetes, because these drugs allow a low hemoglobin A1c to be targeted without any risk of hypoglycemia," they wrote in the editorial.

However, the researchers noted that another possible explanation is that the insulin-treated patients were older with more comorbidities and longer disease duration.

They also cautioned that residual sources of confounding were possible, such as different prescribing patterns for cardiovascular prophylaxis across the hemoglobin A1c groups.

Other limitations of the study included missing data, different timing and methodologies for measuring hemoglobin A1c, and inclusion of patients who could be assigned to both cohorts.

Overall, these results should be a reminder that the "lower is better" paradigm has given way to individualized treatment targets, Bergenstal concluded.

"We need to keep trying to understand the data so we get the right patients into the right A1c targets," he told MedPage Today.

Balkau reported having served as a speaker for sanofi-aventis and on advisory panels for AstraZeneca, Bristol Myers Squibb, Lilly, and sanofi-aventis. Simon reported having served as a speaker for GlaxoSmith Kline, sanofi-aventis, Servier, and on advisory panels for AstraZeneca, Bristol Myers Squibb, GlaxoSmith Kline, and Novartis.

Bergenstal reported receiving research funding and serving on advisory boards for various pharmaceutical companies related to novel diabetes treatments but without any related personal compensation.